Historically, vaccines have been our most potent weapon against viral diseases of medical importance. Development of a vaccine against HIV holds the greatest promise for preventing what will otherwise by a public health disaster of catastrophic proportions. Studies in animal models have not been sufficiently promising tot generate optimism for the prospects of an effective prophylactic vaccine in the foreseeable future. The proposed studies are centered around a radical but promising new strategy= the development of a live-attenuated, multiply-deleted HIV-1 vaccine for prevention of infection and disease. In one sense, the vaccine strategy that we are developing is traditional in that it is a live-attenuated approach. In another sense, it is new in that it uses modern recombinant DNA technology to delete large regions of genetic information from the virus. Major advantages of a live attenuated, multiply deleted HIV-1 vaccine for AIDS include very low cost of production, worldwide availability, and the likelihood that this will be the most effective vaccine that can be made. The proposed experiments will build upon an extensive collection of detailed information accumulated during the initial granting period. Four groups of experienced, productive, interactive researchers will investigate a wide range of issues for further advancement of this approach. Conditions under which live attenuated SIV vaccines do and do not protect will be defined, novel approaches that improve the safety and efficacy profiles will be identified, and procedures that specifically enhance mucosal immunity will be developed. Through these experiments we will begin the understand the mechanisms of protective immunity and what is needed to induce it.